L-cysteine selenium nanoparticles induce apoptosis in ovarian cancer cells by activating the FOXO3a/GADD45A pathway

Selenium nanoparticles (SeNPs) have emerged as promising anticancer agents due to their selective cytotoxicity and ability to modulate oncogenic signaling pathways. In this study, we developed a novel L-cysteine-modified selenium nanoparticles (L-SeNPs) system and investigated its antitumor effects and underlying molecular mechanisms in ovarian cancer cells. Our results demonstrated that L-SeNPs significantly inhibited cell proliferation and clonogenic potential in a dose- and time-dependent manner in A2780 and SKOV3 ovarian cancer cells. Mechanistically, L-SeNPs induced intracellular reactive oxygen species (ROS) accumulation, which subsequently resulted in DNA damage, as indicated by the accumulation of γ-H2AX. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) markedly attenuated L-SeNPs-induced DNA damage, indicating that ROS generation serves as an upstream event in this process. L-SeNPs further triggered mitochondrial apoptosis characterized by activation of Bax, Bak, and cleaved PARP-1, along with downregulation of Bcl-2. Transcriptomic profiling revealed significant enrichment of the FOXO signaling pathway following L-SeNPs treatment, with GADD45A identified as a key upregulated downstream effector. Further mechanistic studies demonstrated that ROS-mediated DNA damage promoted FOXO3a nuclear translocation, leading to transcriptional activation of GADD45A. Functional experiments confirmed that both FOXO3a and GADD45A are essential for L-SeNPs-induced apoptosis, and restoration of GADD45A partially rescued apoptotic activity in FOXO3a-silenced cells, indicating that GADD45A acts downstream of FOXO3a. In conclusion, L-SeNPs exert potent antitumor effects in ovarian cancer cells by inducing ROS-mediated DNA damage and activating the FOXO3a-GADD45A axis, thereby triggering mitochondrial apoptosis and suppressing tumor cell proliferation. These findings provide new mechanistic insights into selenium-based nanomaterials and suggest the FOXO3a-GADD45A pathway as a potential therapeutic target for ovarian cancer treatment.